CC BY
0
286
CHEMICAL PROBLEMS 2025 no. 2 (23) ISSN 2221-8688
NEW FENOFIBRATE DERIVATIVES AS ANTICANCER AND ANTIOXIDANT AGENTS: SYNTHESIS, IN SILICO STUDY AND BIOLOGICAL EVALUATION
Rusul Naeim Mankhi1*, Nabeel A. Abdul-Rida2
1Chemistry Department - College of Pharmacy, University of Misan, Misan City - Iraq 2Chemistry Department, College of Science, University ofAl-Qadisiyha, Diwanyiah, 58002, Iraq *1e-mail: [email protected], 2e-mail: [email protected]
Received 05.09.2024 Accepted 04.11.2024
Abstract: Fenofibrate is a medication derived from fibric acid that is used to treat severe cases of high triglyceride levels and a combination of abnormal lipid levels in individuals who have not shown improvement with nonpharmacological treatments. As part of this research, novel classes of Fenofibrate derivatives were synthesized and evaluated in vitro as anticancer and antioxidant agents. Spectroscopic techniques, including infrared, NMR and elemental analysis, were used to validate their structures conclusively. all products were screened in vitro against cell lines MDA-MB-231. The cytotoxicity assay results revealed that derivatives 5b and 5c exhibited good inhibition for MDA-MB-231. The IC50 values for derivatives 5b and 5c were 79.09 and 128.10 fg/m, respectively. A molecular docking study of the synthetic compounds confirmed the cytotoxicity test results. In addition, the DPPH investigation revealed good antioxidant activity for derivatives 5c and 5e with inhibition percentages of93.85 and 92.31%, respectively, compared to ascorbic acid. Keywords: Fenofibrate, Amide; Antioxidant; Anticancer; Molecular Docking. DOI: 10.32737/2221-8688-2025-2-286-293
Introduction
Fenofibrate, also known as fenoglide or lipofen, is a chlorobenzophenone that is is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid. It has received increasing attention in recent years because of its various activities as an antilipemic drug, an environmental contaminant, a xenobiotic and a geroprotector [1]. In addition to being a useful gout supplement, it helps lower blood uric acid levels [2]. Furthermore, it has pleiotropic actions such as anti-inflammatory [3], against diabetes [4], anti-atherogenic [5], and inhibits the development of liver diseases [6]. On the other hand, Amides also play a key role in medicinal chemistry due to their wide-ranging applications in the pharmaceutical industry. The amide functional group is present in numerous bioactive compounds or drugs, and modifying
amides is a crucial method for optimizing new chemical entities in medicinal chemistry [7]. Studies have shown that amide bonds are very prevalent and intriguing forms of links in both organic synthesis and nature [8-12]. Some of them exhibit a variety of biological activities, such as Antibacterial [13-15], antiviral [16-18], anti-inflammatory [19-21], anticancer [22, 23], antioxidant [24] and anti-Alzheimer activity [25,26], in addition to their importance in the industrial field [27,28]. In this study, we have developed novel prodrugs based on fenofibrate derivatives. Some prodrugs were evaluated for their potential as anti-breast cancer agents, while all were assessed for their antioxidant activity. These actions were examined both theoretically via molecular docking and in vitro experiments.
Experimental part
General information Spectrometer, which runs at 300 MHz, is used to
All chemicals come from Merck and Al- get the 1H-, 13C- and 2D-NMR spectra. A Drich, and the Fourier Transform Varian reference standard in DMSO-d6 solvent is used
CHEMICAL PROBLEMS 2025 no. 2 (23)
www .chemprob.org
to record the spectra. FT-IR spectra were obtained using a Japanese FTIR 8400S Shimadzu Spectrophotometer covering a 400 to 4000 cm-1 range. The elemental analyses (C.H.N.) were determined using the EA 300 C.H.N Element Analyzer's micro-analytical unit. Gallenkamp MFB-600 Melting Point the Stuart apparatus was used to Get the melting points.
Synthesis
Preparation method of fenofibric acid
[29]
A solution of Fenofibrate 1 (5.0g, 13.85mmol) in ethanol (30ml) was treated with sodium hydroxide (0.6 g, 0.01485mmol) dissolved in water (2ml). Afterward, the combination of chemicals was heated to its boiling point at 84 °C and continued at that temperature for 3 hours. The progress of the reaction was tracked by using (TLC) with a solvent mix of hexane and ethyl acetate in a volumetric ratio of 7:3. After cooling to 250C, the reaction mixture was subjected to vacuum distillation to get a residue. Subsequently, the remaining substance was combined with 50 cc of ice-cold water and made acidic by adding dilute hydrochloric acid. The resulting solid product 2 was isolated using filtering and then desiccated with air to get a solid white color. The material yields 92% and a melting point of 180 °C.
Preparation method of acid chloride [30]
A 100mL round-bottom flask was used in a fume hood to combine an excessive amount of thionyl chloride with 4 grams of fenofibric acid 2. The mixture was heated to 60°C for one or two hours. Thionyl chloride was gaseous evaporated at reduced pressure.
General procedure for synthesis of the Fenofibrate derivatives 5a-e [31]
The amine 4 (1equivalent) was dissolved in 15ml of anhydrous DCM. In addition, two moles of triethylamine were added as catalyst. After cooling the mixture to 0°C, a progressive addition of the acid chloride 3 (1equivalent) solution in dichloromethane (DCM) at 0 °C was added gradually. The ice bath was later removed after the addition. The reaction mixture was agitated for 2-5 hours, after which it was washed with a 15 ml hydrochloric acid with a concentration of 0.5 N and subsequently with water. Subsequently, the resultant mixture was desiccated using anhydrous MgSO4. Subsequently, the solvent was evaporated using
decreased pressure, leading to the formation of a solid. The intended product 5a-e was obtained by recrystallizing the crude product from ethanol. 2-(4-(4-chlorobenzoyl) phenoxy)-2-methyl-N-(thiazol-2-yl)propenamidev 5a: Light brown crystals, m.p 96-98°C, yield 75%. FT-IR (cm-1) v: 3379 (N-Hamid), 3078(C-Hat), 1681 (C=O).1H NMR (DMSO-d6, 400 MHz) 5 11.80 - 6.94 (m, 9H), 1.67 (s, 6H). 13C NMR (DMSO-^6, ppm): 5 193.71, 174.91, 172.55, 159.43, 137.98, 137.55, 136.60, 132.28, 131.64, 130.43, 129.05, 118.45, 117.52, 114.55, 80.75, 40.58, 40.37, 40.16, 39.95, 39.74, 39.53, 39.32, 25.09. Elemental Analysis for C20H17ON2O3S: C, 60.54; H, 5.11; Cl, 7.89; N, 6.03; O, 12.56; S, 9.14. 2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)propenamide 5b:
Yellow brown crystals, m.p 152-154°C, yield 89%. FT-IR (cm-1) v: 3309 (N-Hamid), 2970 (CHAr), 1651 (C=O).1H NMR (DMSO-d6, ppm): 5 8.55 (s, 1H), 7.65-7.54 (m,7H), 6.92 (dd, J = 29.0, 8.9 Hz, 5H), 1.55 (s,7H). 13C NMR (DMSO-J6, ppm): 5 193.69, 174.94, 160.02, 159.28, 132.33, 131.65, 131.17, 129.84, 129.71, 129.04, 127.42, 127.05, 118.55, 117.45, 79.37, 40.55, 40.34, 40.13, 39.71, 39.50, 39.29, 25.56. Elemental Analysis for C25H20ON3O3S: C, 63.48; H, 5.31; Cl, 8.11; N, 9.20; O, 9.79; S, 7.18. 2-(4-(4-chlorobenzoyl) phenoxy)-N-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)-2-methylpropanamide 5c: Yellow crystals, m.p 118-120°C, yield 85%. FT-IR (cm-1) v: 3545 (N-Hamid), 3190 (C-Hat), 1651 (C=O)^H NMR (DMSO-d6, ppm): 5 8.56 (s, 1H), 7.82-7.67 (m, 8H), 6.96-6.84 (m, 5H). 13C NMR (DMSO-J6, ppm): 5 193.68, 175.00, 160.16, 159.32, 158.84, 137.47, 136.76, 135.69, 132.28, 130.52, 129.87, 129.60, 129.03, 128.65, 118.56, 117.47, 79.55, 40.58, 40.37, 40.16, 39.95, 39.74, 39.54, 39.33, 25.63. Elemental Analysis for C25H19Q2N3O3S: C, 57.42; H, 4.23; Cl, 12.78; N, 9.33; O, 19.05; S, 7.13. 2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-N-(thiazol-4-yl)propenamide 5d: dark brown crystals, m.p 104-106°C, yield 90%. FT-IR (cm-1) v: 3379 (N-Hamid), 3151 (C-Hat), 1680 (C=0). 1H NMR (DMOS-d6, ppm) 5 10.37 (s, 1H), 7.90-7.61 (m, 8H), 7.03 (d, J = 8.9 Hz, 3H), 1.64 (s, 6H). 13C NMR (DMSO-d6, ppm) 5 193.70, 172.91, 159.42, 143.33, 137.57, 136.56, 132.68, 132.35, 131.65, 130.58, 129.63, 129.05,
120.12, 118.68, 81.57, 40.58, 40.37, 40.16, 39.96, 39.75, 39.54, 39.33, 25.18. Elemental Analysis for C20H17QN2O3S: C, 58.76; H, 5.06; Cl, 9.49; N, 7.72; O, 12.22; S, 7.83. 2-(4-(4-chlorobenzoyl) phenoxy)-2-methyl-N-(1H-1,2,4-triazol-3-yl)propenamide5e: Yellow crystals, m.p 145-147°C, yield 78%. FT-IR (cm-1) v: 3387 (N-Hamid), 3055 (C-Ha), 1647 (C=O).1H NMR (DMSO-d6, ppm): 5 8.42 (s, 1H), 7.56 (d, J = 8.6 Hz, 11H), 1.72 (s, 6H). 13C NMR (DMSO-d6, ppm) 5 193.73, 173.24, 162.77, 159.99, 159.24, 137.59, 136.73, 136.57, 132.30, 131.66, 130.62, 129.77, 129.08, 120.69, 118.71, 117.49, 80.86, 40.57, 40.37, 40.16, 39.95, 39.74, 39.53, 39.32, 24.99, 9.01. Elemental Analysis for C^nC^Os: C, 60.42; H, 5.41; Cl, 8.87; N, 15.33; O, 11.26 Antioxidant assay [32] Antioxidants were identified in a sample using the Blois method. For the control, we dissolved DPPH in methanol, and for the standard, we used ascorbic acid. After making compound solutions of varying concentrations, 2 mL of DPPH solution was added to every sample. After two hours of incubation in a dark chamber, a UV-VIS Shimadzu spectrophotometer was used to analyze the sample's absorbance at 517 nm. An inhibition percentage was used to measure the free radical scavenging activity.
Inhibition %= (control)-A(sample) / A(control) x100
A (control): Absorption of DPPH + solvent (MeOH)
A (sample): Absorption of DPPH + sample (sample test/standard)
The cytotoxicity assay [33]:
Cell lines and culture: A human breast
cancer cell line MDA-MB-231 was grown in RPMI 1640 media with antibiotics and 10% fetal bovine serum. The Iranian National Cell Bank donated this cell line. In a controlled environment with humidity and a concentration of 5% CO2, the cells were kept at 37 °C. MTT cell viability assay: Cell proliferation and viability were assessed using the MTT test in this research. After being harvested, the cells were prepared to have a density of 1.4 x 101 cells/well and then placed onto 96-well plates. Following a day, the cells were exposed to compounds at concentrations ranging from 600 to 7.4 ^g/ml for another day at 37°C with 5% CO2. Each well was supplemented with 100 |il of MTT solution after 24 hours, and the plate was left to incubate at 37°C for a further 4 hours. After that, the cells were shaken in an incubator set at 37°C until all of the crystals had dissolved. The ELISA reader was used to test cell viability, and the dose-response curves were utilized to estimate the concentration of compounds that induced 50% cell death.
Docking study analysis [34]
Molecular docking studies were performed on five synthetic compounds to identify potential binding interactions with placental aromatase cytochrome P450. The PDB database, accessible at https://www.rcsb.org/, was used to get the ID 3EQM. The selected derivatives were first shown in two dimensions before being converted to three dimensions by molecular mechanics. The ligands were subsequently constructed from these three-dimensional structures. The docking study findings, including the binding energy and the receptor configuration in 2D interaction poses, were computed using the MOE 2015.10 program.
Results and discussion
A series of amide derivatives were synthesized by reacting the amine derivatives with acid chloride 3 according to the additionelimination mechanism using CH2CI2 as solvent and triethylamine as catalyst to neutralize the HCl that develops after the amide formation. The
reaction steps and conditions were seen in Scheme 1. The structures of all synthesized compounds were spectroscopically characterized by (IR, 1H-NMR, 13C-NMR) and micro-elements analysis. The spectroscopic data obtained were included in the experimental section.
Scheme 1: The experimental steps for synthesis of compounds 5a-e
Biological activity
In order to determine whether chemicals may bind to a certain protein (PDB: 3eqm) and hence prevent breast cancer, the software MOE 2015 was used. We chose the top compounds
(highlighted in yellow) from Table 1 for in vitro testing because they show strong activity against the examined protein. Protein binding to these produced compounds is seen in Fig. 1 below:
PDB : 3eqm
PDB: 3eqm
Fig. 1. The interaction mode of compounds (5b, 5c) with active site amino acids of the protein
(PDB 3EQM)
Table 1. Molecular docking results for prepared derivatives 5a-e as anti-cancer agents.
■a ^ Target protein: Oxidoreductase (3EQM)
S is s -o o s Position of interaction
a t S o -J U w E Binding Kcal/mol RMSD Ligand Receptor Interaction Distance (A) E (Kcal/mol)
5a -8.5739 1.9765 6-ring CA (CYS 437) pi-H 3.83 -0.9
O (40) SG (CYS 437) H-donor 3.45 -0.9
5b -10.1417 1.9389 O (40) N (ALA 438) H-acceptor 3.01 -0.9
5-ring CB (ALA 438) pi-H 4.21 -0.9
5-ring CG2 (VAL 370) pi-H 4.11 -0.7
5c -10.3244 1.3256 5-ring CB (CYS 437) pi-H 4.01 -0.6
6-ring CA (GLY 439) pi-H 4.18 -0.7
5d -9.2826 1.9454 S (27) O (PRO 429) H-donor 3.60 -0.9
N (26) SD (MET 374) H-donor 3.82 -1.1
5e -8.3276 1.3102 6-ring CG1 (ILE 133) pi-H 4.07 -0.8
6-ring N (ALA 438) pi-H 4.85 -0.7
Cytotoxicity of synthesized compounds
The anticancer effects of the derivatives 5b and 5c were evaluated against the cancer cell line MDA-MB-231 in vitro using the conventional
MTT technique. The figures in Fig. 1 represent the cell viability percentages of compounds 5b and 5c.
Fig. 2. Cell viability percentage of compounds (5b, 5c) against cancer cell line MDA-MB-231.
Table 2. The cytotoxicity results for compounds (5b, 5c) against the MDA-MB-231 cancer cell
line.
5b: IC50= 79.09 ^ ^/mL
Concentration (^g/mL) 7.4 22.22 66.66 200 600
Absorption at 57 nm 0.633 0.738 0.651 0.651 0.462 0.633 0.738 0.651 0.651 0.462
Viability (%) 85.54 99.73 87.97 87.97 62.43 85.54 99.73 87.97 87.97 62.43
Average Viability (%) 92.64 87.97 64.93 16.01 7.36
Standard Deviation (±) 10.03 0.00 3.54 0.67 0.48
5c: IC50= 128.10 ^g/mL
Concentration (^g/mL) 7.4 22.22 66.66 200 600
Absorption at 57 nm 0.615 0.647 0.594 0.561 0.458 0.615 0.647 0.594 0.561 0.458
Viability (%) 83.11 87.43 80.27 75.81 61.89 83.11 87.43 80.27 75.81 61.89
Average Viability (%) 85.27 78.04 61.22 52.50 19.66
Standard Deviation (±) 3.06 3.15 0.96 1.43 1.05
Table 3. DPPH Radical Scavenging Activity of the Synthesized Compound 5a-e
Compound s % RSA (radical scavenging activity) at seven different concentrations (^g/ml)
1000 800 750 400 200 50 12.4
5a 75.54 68.63 62.99 55.20 51.46 46.12 39.34
5b 69.35 62.43 52.30 49.87 32.22 29.19 20.33
5c 93.85 90.74 86.77 64.98 51.90 32.32 25.96
5d 79.10 74.22 68.64 57.31 48.34 37.56 30.45
5e 92.31 90.50 86.83 81.86 74.92 66.28 58.11
Ascorbic acid 99.77 98.72 97.33 95.14 93.67 92.35 91.12
Antioxidant Activity
The antioxidant activity of the produced compounds was evaluated using the DPPH assay, which is a well-used approach. The test
determines how well the materials donate hydrogen to neutralize DPPH radicals. An increase in radical scavenging activity is shown by a change in color, which occurs when
antioxidant drugs convert DPPH into a stable than that of the conventional ascorbic acid, as diamagnetic molecule. The antioxidant activity shown in Table 3. of all the produced compounds was much higher
Conclusions
In summary, amide derivatives were produced from compounds that included fenofibrate and sulfa drugs. These compounds were purified, their structures were characterized, and their biological activity was assessed in vitro as an antioxidant and anticancer agent. The results of the cytotoxicity test point to the possibility of using compounds 2-(4-(4-
chlorobenzoyl)phenoxy)-2-methyl-N-(5-phenyl-1,3,4-thiadiazol-2-yl)propenamide5b, and 2-(4-(4-chlorobenzoyl) phenoxy)-N-(5-(4-
chlorophenyl)-1,3,4-thiadiazol-2-yl)-2-methyl propanamide 5c as antiproliferative agents of MDA-MB-231cell lines. At the same time, the DPPH test results showed that some new amide derivatives have strong antioxidant activity.
References
1. Tenenbaum A., Fisman E.Z. Fibrates are an essential part of modern anti-dyslipidemic arsenal: spotlight on atherogenic dyslipidemia and residual risk reduction. Cardiovasc Diabetol. 2012, Vol. 11, 125, 10 pages. doi: 10.1186/1475-2840-11-125
2. Abdul-Rida N.A., Sayyah M.H., Jaber Q.A.H. Synthesis, characterization, efficiency evaluation of some novel triazole derivatives as acid corrosion inhibitors. Int. J. Corr. Scale Inhib, 2023, Vol. 12(1), p. 101-125. doi:10.17675/2305-6894-2023-12-1-6
3. McKeage K., Keating G.M., Bhatnagar D., Elam M.B., Farnier M., Mohiuddin S.M. Fenofibrate: A review of its use in dyslipidaemia. Drugs, 2011, Vol. 71(14), p. 1917-1946. doi:10.2165/11208090-000000000-00000
4. Jin L., Hua H., Ji Y., Jia Z., Peng M., Huang S. Anti-inflammatory role of fenofibrate in treating diseases. Biomol Biomed. 2023, Vol. 23(3), p. 376-391. doi: 10.17305/bb.2022.8534
5. Holm L.J., Haupt-Jorgensen M., Giacobini J.D., Hasselby J.P., Bilgin M., Buschard K. Fenofibrate increases very-long-chain sphingolipids and improves blood glucose homeostasis in NOD mice. Diabetologia, 2019, Vol. 62(12), p. 2262-2272. doi:10.1007/s00125-019-04973-z
6. Xu N., Wang Q., Jiang S., Wang Q., Hu W., Zhou S., Zhao L., Xie L., Chen J., Welsstein A., Lai E.Y. Fenofibrate improves vascular endothelial function and contractility in
diabetic mice. Redox Biol. 2019, Vol. 20, p. 87-97. doi:10.1016/j.redox.2018.09.024
7. Kumari S., Carmona A.V., Tiwari A.K., Trippier P.C. Amide Bond Bioisosteres: Strategies, Synthesis, and Successes. J. Med. Chem. 2020, Vol. 63(21), p. 12290-12358. doi: 10.1021/acs.jmedchem.0c00530
8. Pattabiraman V.R., Bode J.W. Rethinking amide bond synthesis. Nature, 2011, Vol. 480(7378), p. 471-479. doi: 10.1038/nature 10702
9. de Figueiredo R.M., Suppo J.S., Campagne J.M. Nonclassical Routes for Amide Bond Formation. Chem Rev. 2016, Vol. 116(19), p. 12029-12122. doi: 10.1021/acs.chemrev.6b00237
10. Scheidt K. Organic chemistry: Amide bonds made in reverse. Nature. 2010, Vol. 465(7301), p.1020-1022. doi: 10.1038/4651020a
11. Al-Radha N.A.A., Jaber Q.A.H. Synthesis of Some Substituted Pyrimidines Derived from 3-Acetyl Coumarin. Asian J. Chem., 2015, Vol. 27(10), p. 3687-3691. doi:10.14233/ajchem.2015.18925
12. Ahmed A.S., Ahmed A.J.M. New p-Aminodiphenylamine Amide Compounds: Design, Synthesis and Anti P-lactamases Activity Evaluation. Chemical Problems, 2024, Vol. 22(1), p. 20-32. doi: 10.32737/2221 -8688-2024-1-20-32
13. Chen D., Cheng Y., Shi L., Gao X., Huang Y., Du Z. Design, Synthesis, and Antimicrobial Activity of Amide Derivatives Containing
292
Cyclopropane. Molecules, 2024, Vol. 29(17), p. 4124.
doi:10.3390/molecules29174124
14. Limwongyut J., Moreland A.S., Nie C., Read de Alaniz J., Bazan G.C. Amide Moieties Modulate the Antimicrobial Activities of Conjugated Oligoelectrolytes against Gram-negative Bacteria. ChemistryOpen. 2022, Vol. 11(2), e202100260. doi: 10.1002/open.202100260
15. Abidin A.Z., Norrrahim M.N.F., Shakrin N.N.Sh.M., Ibrahim B., Abdullah N., Abdul Rashid J.I., Kasim N.A.M., Ahmad Shah N.A. Amidine containing compounds: Antimicrobial activity and its potential in combating antimicrobial resistance. Heliyon, 2024, Vol. 10(15), e32010. doi: 10.1016/j .heliyon.2024.e32010
16. Gazquez Casals A., Berkowitz A.J., Yu A.J., Waters H.E., Schiavone D.V., Kapkayeva D M., Morrison L.A., Murelli R.P. Antiviral activity of amide-appended a-hydroxytropolones against herpes simplex virus-1 and -2. RSC Adv. 2023, Vol. 13(13), p. 8743-8752. doi: 10.1039/d2ra06749h
17. Li Q., Lomonosova E., Donlin M.J., Cao F., O'Dea A., Milleson B., Berkowitz A.J., Baucom J.-Ch., Stasiak J.P., Schiavone D.V., Abdelmessih R.G., Lyubimova A., Fraboni A.J., Bejcek L.P., Villa J.A., Gallicchio E., Murelli R.P., Tavis J.E. Amide-containing a-hydroxytropolones as inhibitors of hepatitis B virus replication. Antiviral Res. 2020, Vol. 177, 104777. doi:10.1016/j.antiviral.2020.104777
18. Baev D.S., Blokhin M.E., Chirkova V.Y., Belenkaya S.V., Luzina O.A., Yarovaya O.I., Salakhutdinov N.F., Shcherbakov D.N. Triterpenic Acid Amides as Potential Inhibitors of the SARS-CoV-2 Main Protease.Molecules. 2022, Vol. 28(1), 303. doi:10.3390/molecules28010303
19. Xing T., Yu S., Qin M., Zhang M., Ma Y., Xiao Z. Synthesis, anti-inflammatory activity, and conformational relationship studies of chromone derivatives incorporating amide groups. Bioorg Med. Chem. Lett. 2023, Vol. 96, 129539. doi:10.1016/j.bmcl.2023.129539
20. Nedeljkovic N., Dobricic V., Boskovic J., Vesovic M., Bradic J., Andic M., Kocovic
A., Jeremic N., Novakovic J., Jakovljevic V., Vujic Z., Nikolic M. Synthesis and Investigation of Anti-Inflammatory Activity of New Thiourea Derivatives of Naproxen. Pharmaceuticals (Basel). 2023, Vol. 16(5), 666. doi: 10.3390/ph16050666
21. Chen P., Yang J., Zhou Y., Li X., Zou Y., Zheng Zh., Guo M., Chen Zh., Cho W-J., Chattipakorn N., Wu W., Tang Q., Liang G. Eur. J Med. Chem., 2023, Vol. 259, 115706. doi:10.1016/j.ejmech.2023.115706
22. Jaber Q.A., Shentaif A.H., Almajidi M., Ahmad I., Patel H., Azad A.K., Alnasser S.M., Alatawi H.A., Menaa F., Alfaifi S.Y.M., Rahman M.M., Ali M.M., Aditya Rao S.J. Synthesis, Structure, and In Vitro Pharmacological Evaluation of some New Pyrimidine-2-Sulfonamide Derivatives and Their Molecular Docking Studies on Human Estrogen Receptor Alpha and CDK2/Cyclin Proteins. Russ. J. Bioorg. Chem., 2023, Vol. 49, p. S106-S118. doi.org/10.1134/S1068162023080095
23. Nabeel A.A., Kawther M. T. New Chalcone Derivatives as Anticancer and Antioxidant Agents: Synthesis, Molecular Docking Study and Biological Evaluation. Chemical Problems, 2024, Vol. 22(2), p. 177-186. doi:10.32737/2221 -8688-2024-2-177-186
24. Nabeel A.A.R., Islam H.T. Synthesis Characterization in Silico and in Vitro Study of New 1, 2, 3-Triazole Derivatives as Antioxidant Agents. Chemical Problems, 2023, Vol. 21(4), p. 343-352. doi:10.32737/2221-8688-2023-4-343-352
25. Nabeel Z., Jaber Q.A.H., Abdul-Rida N.A. Novel Benzo[/]coumarin Derivatives as Probable Acetylcholinesterase Inhibitors: Synthesis, In Vitro, and In Silico Studies for Evaluation of Their Anti-AChE Activity. Indones. J. Chem, 2022, Vol. 22(1), p. 3546. doi:10.22146/ijc.65663
26. Waseem W., Anwar F., Saleem U., Ahmad B., Zafar R., Anwar A., Jan M.S., Rashid U., Sadiq A., Ismail T. Prospective Evaluation of an Amide-Based Zinc Scaffold as an Anti-Alzheimer Agent: In Vitro, In Vivo, and Computational Studies. ACS Omega. 2022. Vol. 7(30), p. 26723-26737.
doi: 10.1021/acsomega.2c03058
27. Al-Edan A.K., Roslam Wan Isahak W.N., Che Ramli Z.A., Al-Azzawi W.Kh.,
Kadhum A.A.H., Jabbar H.S., Al-Amiery A. Palmitic acid-based amide as a corrosion inhibitor for mild steel in 1M HCl. Heliyon. 2023, Vol. 9(4), e14657. doi: 10.1016/j .heliyon.2023.e14657
28. Ghonem N.S., Assis D.N., Boyer J.L. Fibrates and cholestasis. Hepatology (Baltimore, MD), 2015, Vol. 62(2), p. 635643. doi:10.1002/hep.27744
29. Majethia G.N., Haq W., Balendiran G.K. A facile synthesis of 2-(4-((4-chlorophenyl)(hydroxy)methyl) phenoxy)-2-methylpropanoic acid: Metabolite of anti-hyperlipidemic drug Fenofibrate. Results in Chemistry, 2024, Vol. 7, 101282. doi: 10.1016/j .rechem.2023.101282
30. Teeba S.K., Mohanad M.K., Abbas J.A. Synthesis, characterization and investigation of antibacterial activity for some new functionalized luminol derivatives. Bull. Chem. Soc. Ethiop, 2023, Vol. 37(1), p.
159-169. doi:10.4314/bcse.v37i1.13
31. Zhang L., Wang X.-J., Wang J., Grinberg N., Krishnamurthy D.K., Senanayake C.H. An improved method of amide synthesis using acyl chlorides. Tetrahedron Letters, 2009, Vol. 50(24), p. 2964-2966. doi:10.1016/j.tetlet.2009.03.220
32. Baliyan S., Mukherjee R., Priyadarshini A., Vibhuti A., Gupta A., Pandey R.P., Chang C.M., Determination of Antioxidants by DPPH Radical Scavenging Activity and Quantitative Phytochemical Analysis of Ficus religiosa. Molecules, 2022, Vol. 27(4), p. 1326. doi:10.3390/molecules27041326
33. Bahuguna A., Khan I., Bajpai V.K., Kang S.C. MTT assay to evaluate the cytotoxic potential of a drug. Bangladesh Journal of Pharmacology, 2017, Vol. 12(2), p. 8. doi:10.3329/bjp.v12i2.30892
34. Rizvi S.M., Shakil S., Haneef M. A simple click by click protocol to perform docking: AutoDock 4.2 made easy for non-bioinformaticians. EXCLI J., 2013, Vol. 12, p. 831-857.
